Cardiovascular adverse events in phase 3 trials of BTKis
| . | Study . | N Treatment Arm . | Study Population . | Median Follow-up, mo . | Atrial Fibrillation, n (%) . | Hypertension, n (%) . | Ventricular Arrhythmias, n (%) . | |||
|---|---|---|---|---|---|---|---|---|---|---|
| All grades . | Grade ≥3 . | All grades . | Grade ≥3 . | All grades . | Grade ≥3 . | |||||
| Ibrutinib | RESONATE9 | 195 ibrutinib | RR CLL | 9.4 | 10 (5) | 6 (3) | NR | NR | NR | NR |
| 191 ofatumumab | 1 (0) | 0 (0) | NR | NR | NR | NR | ||||
| Long-term follow up10 | 195 ibrutinib | RR CLL | 41.0 | 24 (12) | 12 (6) | 41 (21) | 18 (9) | 2 (1) | 0 (0) | |
| RESONATE-28 | 135 ibrutinib | TN CLL/SLL; ≥65 yr | 17.4 | 8 (6) | 2 (1) | 19 (14) | 6 (4) | NR | NR | |
| 132 chlorambucil | 1 (1) | 0 (0) | NR | 0 (0) | NR | NR | ||||
| Long-term follow-up7 | 135 ibrutinib | TN CLL/SLL; ≥65 yr | 57.0 | 22 (16) | 7 (5) | 35 (26) | 12 (9) | NR | NR | |
| ECOG19125 | 352 ibrutinib + rituximab | TN CLL/SLL; ≤70 yr | 33.6 | NR | 13 (4) | NR | 66 (19) | NR | 1 (0) | |
| 158 FCR | 5 (3) | 2 (1) | NR | 13 (8) | NR | 0 (0) | ||||
| HELIOS27 | 287 ibrutinib | RR CLL/SLL | 17.0 | 21 (7) | NR | NR | NR | NR | 3 (1) | |
| 287 BR | 7 (2) | NR | NR | NR | NR | 0 (0) | ||||
| Alliance A0412026 | 180 ibrutinib monotherapy | TN CLL; ≥65 yr | 38.0 | 31 (17) | 17 (9) | NR | 53 (29) | NR | 1 (1) | |
| 181 ibrutinib + rituximab | 25 (14) | 10 (6) | NR | 61 (34) | NR | 0 (0) | ||||
| 176 BR | 5 (3) | 5 (3) | NR | 25 (14) | NR | 0 (0) | ||||
| iLLUMINATE4 | 113 ibrutinib + obinutuzumab | TN CLL/SLL; ≥65 yr or unfit | 31.3 | 8 (7) | 6 (5) | 15 (13) | 4 (4) | NR | NR | |
| 115 Clb-O | 0 (0) | 0 (0) | 5 (4) | 4 (3) | NR | NR | ||||
| Acalabrutinib | ASCEND36 | 154 acalabrutinib | RR CLL | 16.1 | 8 (5) | 2 (1) | 5 (3) | 3 (2) | 0 (0) | 0 (0) |
| 118 idelalisib + rituximab | 4 (3) | 1 (1) | 5 (4) | 1 (1) | 0 (0) | 0 (0) | ||||
| 35 BR | 1 (3) | 1 (3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||||
| ELEVATE-TN26 | 179 acalabrutinib monotherapy | — | — | 7 (4) | 0 (0) | 8 (4) | 4 (2) | 0 (0) | 0 (0) | |
| 178 acalabrutinib + obinutuzumab | 6 (3) | 1 (1) | 13 (7) | 5 (3) | 0 (0) | 0 (0) | ||||
| 177 Clb-O | 1 (1) | 0 (0) | 6 (4) | 5 (3) | 0 (0) | 0 (0) | ||||
| ELEVATE-RR29 | 265 ibrutinib | RR CLL with del17 or del11 mutations | 40.9 | 42 (16) | 9 (3) | 60 (23) | 23 (9) | 1 (0) | 1 (0) | |
| 268 acalabrutinib | 25 (9) | 12 (4) | 23 (9) | 11 (4) | 0 (0) | 0 (0) | ||||
| Zanubrutinib | ALPINE22,38 | 208 ibrutinib | RR CLL/SLL | 15.0 | 21 (10) | NR | NR | NR | NR | NR |
| 207 zanubrutinib | 5 (2.5) | NR | NR | NR | NR | NR | ||||
| ASPEN30 | 98 ibrutinib | WM | 37.0 | 15 (15) | 4 (4) | 16 (16) | 11 (11) | NR | NR | |
| 101 zanubrutinib | 2 (2) | 0 (0) | 11 (11) | 6 (6) | NR | NR | ||||
| . | Study . | N Treatment Arm . | Study Population . | Median Follow-up, mo . | Atrial Fibrillation, n (%) . | Hypertension, n (%) . | Ventricular Arrhythmias, n (%) . | |||
|---|---|---|---|---|---|---|---|---|---|---|
| All grades . | Grade ≥3 . | All grades . | Grade ≥3 . | All grades . | Grade ≥3 . | |||||
| Ibrutinib | RESONATE9 | 195 ibrutinib | RR CLL | 9.4 | 10 (5) | 6 (3) | NR | NR | NR | NR |
| 191 ofatumumab | 1 (0) | 0 (0) | NR | NR | NR | NR | ||||
| Long-term follow up10 | 195 ibrutinib | RR CLL | 41.0 | 24 (12) | 12 (6) | 41 (21) | 18 (9) | 2 (1) | 0 (0) | |
| RESONATE-28 | 135 ibrutinib | TN CLL/SLL; ≥65 yr | 17.4 | 8 (6) | 2 (1) | 19 (14) | 6 (4) | NR | NR | |
| 132 chlorambucil | 1 (1) | 0 (0) | NR | 0 (0) | NR | NR | ||||
| Long-term follow-up7 | 135 ibrutinib | TN CLL/SLL; ≥65 yr | 57.0 | 22 (16) | 7 (5) | 35 (26) | 12 (9) | NR | NR | |
| ECOG19125 | 352 ibrutinib + rituximab | TN CLL/SLL; ≤70 yr | 33.6 | NR | 13 (4) | NR | 66 (19) | NR | 1 (0) | |
| 158 FCR | 5 (3) | 2 (1) | NR | 13 (8) | NR | 0 (0) | ||||
| HELIOS27 | 287 ibrutinib | RR CLL/SLL | 17.0 | 21 (7) | NR | NR | NR | NR | 3 (1) | |
| 287 BR | 7 (2) | NR | NR | NR | NR | 0 (0) | ||||
| Alliance A0412026 | 180 ibrutinib monotherapy | TN CLL; ≥65 yr | 38.0 | 31 (17) | 17 (9) | NR | 53 (29) | NR | 1 (1) | |
| 181 ibrutinib + rituximab | 25 (14) | 10 (6) | NR | 61 (34) | NR | 0 (0) | ||||
| 176 BR | 5 (3) | 5 (3) | NR | 25 (14) | NR | 0 (0) | ||||
| iLLUMINATE4 | 113 ibrutinib + obinutuzumab | TN CLL/SLL; ≥65 yr or unfit | 31.3 | 8 (7) | 6 (5) | 15 (13) | 4 (4) | NR | NR | |
| 115 Clb-O | 0 (0) | 0 (0) | 5 (4) | 4 (3) | NR | NR | ||||
| Acalabrutinib | ASCEND36 | 154 acalabrutinib | RR CLL | 16.1 | 8 (5) | 2 (1) | 5 (3) | 3 (2) | 0 (0) | 0 (0) |
| 118 idelalisib + rituximab | 4 (3) | 1 (1) | 5 (4) | 1 (1) | 0 (0) | 0 (0) | ||||
| 35 BR | 1 (3) | 1 (3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||||
| ELEVATE-TN26 | 179 acalabrutinib monotherapy | — | — | 7 (4) | 0 (0) | 8 (4) | 4 (2) | 0 (0) | 0 (0) | |
| 178 acalabrutinib + obinutuzumab | 6 (3) | 1 (1) | 13 (7) | 5 (3) | 0 (0) | 0 (0) | ||||
| 177 Clb-O | 1 (1) | 0 (0) | 6 (4) | 5 (3) | 0 (0) | 0 (0) | ||||
| ELEVATE-RR29 | 265 ibrutinib | RR CLL with del17 or del11 mutations | 40.9 | 42 (16) | 9 (3) | 60 (23) | 23 (9) | 1 (0) | 1 (0) | |
| 268 acalabrutinib | 25 (9) | 12 (4) | 23 (9) | 11 (4) | 0 (0) | 0 (0) | ||||
| Zanubrutinib | ALPINE22,38 | 208 ibrutinib | RR CLL/SLL | 15.0 | 21 (10) | NR | NR | NR | NR | NR |
| 207 zanubrutinib | 5 (2.5) | NR | NR | NR | NR | NR | ||||
| ASPEN30 | 98 ibrutinib | WM | 37.0 | 15 (15) | 4 (4) | 16 (16) | 11 (11) | NR | NR | |
| 101 zanubrutinib | 2 (2) | 0 (0) | 11 (11) | 6 (6) | NR | NR | ||||
BR, bendamustine plus rituximab; Clb-O, chlorambucil plus obinutuzumab; FCR, fludarabine, cyclophosphamide, and rituximab; SLL, small lymphocytic lymphoma; TN, treatment-naïve.
Italics denote the non-BTKi comparator arm of the trial.